Increased antipsychotic drug concentration in hospitalized patients with mental disorders following COVID-19 infection: a call for attention

Purpose Examine the alterations in antipsychotic concentrations following coronavirus disease-2019 (COVID-19) infection among hospitalized patients with mental disorders and conduct an analysis of the factors influencing these changes. Methods Data were collected from inpatients at Beijing Huilongguan Hospital between December 12, 2022, and January 11, 2023, pre- and post-COVID-19. Based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 329 inpatients with mental disorders were included (3 with incomplete data excluded). Primary outcomes assessed changes in antipsychotic concentrations pre- and post-COVID-19, while secondary outcomes examined factors linked to concentration increases and antipsychotic dose adjustments. Results Clozapine (P < 0.001), aripiprazole (P < 0.001), quetiapine (P = 0.005), olanzapine (P < 0.001), risperidone (P < 0.001), and paliperidone (P < 0.001) concentrations increased post-COVID-19 in patients with mental disorders. Notably, clozapine concentration surpassing pre-infection levels was highest. Clozapine users were more likely to adjust their dose (50.4%) compared to olanzapine (17.5%) and other antipsychotics. Moreover, traditional Chinese patent medicines and antibiotics during COVID-19 infection were associated with antipsychotic reduction or withdrawal (OR = 2.06, P = 0.0247; OR = 7.53, P = 0.0024, respectively). Conclusion Antipsychotic concentrations in hospitalized patients with mental disorders increased after COVID-19 infection, that may be related not only to COVID-19, but also to the use of Chinese patent medicines during infection. The pre-infection concentration and types of antipsychotics, patient’s gender, and combination of traditional Chinese medicine or antibiotics, were factors found to correlate with increased drug concentrations and necessitate dose adjustments.


Introduction
In 2019, with the rapid spread of the coronavirus disease-2019 (COVID-19) worldwide, the World Health Organization announced that this will be an extremely serious public health event, posing a huge threat to the health and safety of people worldwide.Patients with mental disorders constitute a vulnerable group in society and should be provided more attention and care when facing the disease.Especially for patients diagnosed with severe mental disorders pre-infection, the risk of infection, disease severity, and post-infection mortality are significantly increased (1).The COVID-19 epidemic has had a serious negative impact on the lives and treatment of people with mental disorders (2)(3)(4).Moreover, the ensuing psychological pressure has produced many adverse factors for disease development (5,6).
Because of the disease characteristics of patients with mental disorders, they need to take antipsychotics for a long time to maintain a normal life, and the stability of their concentration is undoubtedly an important factor in maintaining disease stability (7).Few cases have been reported globally in patients with mental disorders who received significantly elevated clozapine concentrations after COVID-19 (8)(9)(10).Additionally, studies have demonstrated that antipsychotics may exacerbate COVID-19 symptoms, which are mainly related to clozapine-induced granulocytopenia, a side effect of the drug (11,12).Therefore, concentration control should be performed with caution.Simultaneously, an expert consensus on the use of clozapine during the COVID-19 pandemic recommends that the clozapine dosage be halved in patients with COVID-19 to avoid drug toxicity at elevated concentrations and reduce the occurrence of side effects (13).A Canadian study has reported that patients with mental disorders after COVID-19 had varying degrees of adjustment to antipsychotic medication (14).
Clozapine metabolism is mainly mediated by the cytochrome CYP1A2 enzyme (15) which is inhibited by inflammation, leading to a significant increase in clozapine levels during infection (16).In addition to clozapine, various first-line antipsychotics are used, most of which are also involved in biological transformation by P450 enzymes (17,18).Therefore, antipsychotics may interact with the infection and treatment of COVID-19, resulting in changes in the drug concentration, which may affect drug efficacy and safety.However, no studies have analyzed the correlation between the concentrations of other antipsychotics and COVID-19.Therefore, the present study mainly focused on changes in antipsychotic concentrations mediated by the P450 enzymes (including clozapine, quetiapine, olanzapine, aripiprazole, risperidone, and paliperidone).We aimed to investigate the impact of COVID-19 infection on antipsychotic concentrations in patients with mental disorders, with the goal of providing corresponding recommendations for adjusting therapy regimens and monitoring plasma levels of antipsychotics.

Participants
In this study, the patients with mental disorders who were hospitalized at Beijing Huilongguan Hospital and infected with COVID-19 during their hospitalization from December 12, 2022 to January 11, 2023 were retrospectively selected.All participants were from the COVID-19-infected areas of the hospital.Patients in the infected areas need to be isolated and restricted in their range of activities.According to the following inclusion and exclusion criteria, a total of 329 patients were enrolled in the study.
The inclusion criteria were as follows: (

Procedures General data collection
General demographic information collected included age, sex, family history, smoking status, and underlying diseases.The clinical data related to mental illness included diagnosed illness, age at first onset, total duration of illness, and medication (type of antipsychotic used, whether it was combined with other psychotropic drugs, drugs it was combined with, daily dose of the main antipsychotic, whether it was reduced, and daily dose after reduction).

Collection of clinical data related to COVID-19
The post-infection clinical symptoms of the patients, including 11 major and other symptoms, were collected according to the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 9) in China (19).Information on the highest body temperature within 14 days post-infection and hematological analysis results (including white blood cells and lymphocytes) within 14 days of infection was also collected.

Drug concentration
At baseline, the patients' drug concentrations within 1 month prior to infection were collected (for patients prescribed antipsychotics, we routinely monitor drug concentrations on a monthly basis to assess therapeutic adherence and ensure safety; and patients who did not adjust their drug dosage were screened out based on diagnosis and treatment records).Four milliliters of venous blood was extracted and collected using a disposable vacuum sampling vessel (without additives).After centrifugation, serum was collected.And its concentration was determined by latex immunonephelometry using a Beckman Coulter AU5800 biochemical analyzer (Beckman Coulter, Inc., Brea, CA, USA).
To collect drug concentrations post-infection, measurements were taken 14 days after the onset of COVID-19 symptoms.Most patients experienced significant remission of symptoms by this time (20).

Analytic strategy
Descriptive statistical analyses were performed on the general demographic and clinical data.Age, age at first onset, daily dose of antipsychotics used pre-and post-infection, concentration pre-and post-infection, rate of change of concentration, and time from monitoring of concentration to symptom onset are represented as means and standard deviations.Statistical data on sex, body temperature, and concentration range pre-and post-infection are expressed as numbers (n) and proportions.Serum concentrations of clozapine, aripiprazole, olanzapine, quetiapine, risperidone, and paliperidone were compared pre-and post-infection, the t test was used for data conforming to normal distribution, and the rank sum test was used for data not conforming to normal distribution.
Considering that the reference ranges of concentration of different drugs are quite different, there was no obvious significance in simply comparing the figures with elevated concentrations.Meanwhile, the supratherapeutic concentrations is more meaningful for reduce or discontinue the dosage.Therefore, in this study, we used the concentration reference range as the uniform reference standard.According to AGNP, concentrations of antipsychotic were divided into three levels, subtherapeutic concentrations, within the range of therapeutic concentrations and supratherapeutic concentrations for comparison between preand post-infection.And the formula "(Infection_TDM -Baseline_TDM) ÷ Baseline_TDM x 100%" was used to calculate the percentage of patients whose antipsychotic concentrations postinfection exceed the concentration range pre-infection.The chisquare test was used to compare different antipsychotic concentrations.Based on the AGNP, the concentration was divided into two categories: below or equal to and above the recommended range, which was the dependent variable.A logistic regression analysis was conducted to determine whether the drug dose was adjusted as a dependent variable, individual factors such as age, sex, and drug type were the independent variables, and the association between the independent and dependent variables was analyzed.
All data were analyzed using the Statistical Package for the Social Sciences version 26.0, and significance was set at P < 0.05.Participants with incomplete data were excluded from the statistical analysis.

Ethical consideration
The research has been approved by the Ethics Committee of Beijing HuiLongGuan Hospital (approval number: 2022-22-KE), and informed consent was signed by each participant.This study was conducted in accordance with the Declaration of Helsinki.
According to the AGNP, concentrations of antipsychotic were divided into three levels, subtherapeutic concentrations, within the range of therapeutic concentrations and supratherapeutic concentrations for comparison between pre-and post-infection.The results revealed that the proportion of individuals whose concentrations of clozapine, aripiprazole, quetiapine, olanzapine, risperidone, and paliperidone were supratherapeutic concentrations increased after COVID-19 (Figure 2A).However, among patients who used antipsychotic drugs and were infected with COVID-19, the percentage of patients whose clozapine concentration exceeded the pre-infection concentration range was the highest (Figure 2B).

Factors affecting antipsychotic concentrations and dosage adjustments
In the logistic regression model, the results revealed that the drug concentration post-infection significantly correlated with the type of antipsychotic and baseline drug concentrations.Compared with patients receiving quetiapine, those receiving clozapine as the main antipsychotic had an increased risk of elevated clozapine concentrations post-infection (odds ratios [OR] = 12.94, P = 0.0158).Compared with patients within the range of therapeutic concentrations, those with subtherapeutic concentration pre-infection had a reduced risk of elevated concentrations post-infection (OR = 0.08, P < 0.0001), and those with supratherapeutic concentrations preinfection had an increased risk of elevated concentrations postinfection (OR = 33.45,P < 0.0001).Age, sex, body temperature, smoking status, and concomitant medication were not significantly associated with the changes in drug concentration post-infection.However, the use of Traditional Chinese patent medicines (mainly Lianhua Qingwen Capsules and Jinhua Qinggan Granules; please refer to the Supplementary Materials for detailed types of drugs) in patients with mental disorders undergoing symptomatic treatment for COVID-19 was identified as a risk factor for increasing the concentration of antipsychotic drugs (OR = 2.55, P = 0.0042) (Table 2).
The results revealed that the pre-infection drug concentration, sex, and antipsychotic type were significantly associated with whether patients underwent major antipsychotic dose adjustment.Among them, men were more likely to require dose adjustments after a drug concentration increase (OR =2.67, P =0.005) (Table 3).
Patients receiving clozapine were more likely to adjust their dose after a concentration increase (OR = 6.58,P < 0.0001), whereas those using olanzapine were less likely to require dose adjustment after a concentration increase (OR = 0.63, P = 0.0166).Patients with preinfection subtherapeutic concentration were less likely to require dose adjustment after a drug concentration increase (OR = 0.31, P < 0.0001).Patients with pre-infection supratherapeutic concentrations were more   3).

Discussion
This study aimed to explore the effects of COVID-19 on antipsychotic concentrations in patients with mental disorders.The concentrations of various antipsychotics increased to varying degrees after COVID-19, which is consistent with the results of previous studies (22).Inflammation can downregulate transporters and drugmetabolizing enzymes, alter plasma protein binding, which in turn affects the absorption, distribution, and clearance of drugs, thereby contributing to an increase in antipsychotic drug serum levels due to a potential slowdown in their metabolism (23-25).Higher concentrations of antipsychotics were associated with increased incidents of somnolence and sedation.Furthermore, there was a higher frequency of reported adverse drug reactions or patient complaints that might be attributed to these heightened levels.Nevertheless, patients' psychiatric symptoms may seemingly improve "relatively better" due to either the novel coronavirus infection or elevated antipsychotic levels, which could inadvertently lead clinicians to neglect the ongoing management of their psychiatric condition.
Consequently, heightened vigilance is imperative for psychiatrists to meticulously monitor antipsychotic concentrations and adverse effects, and dynamically assess changes in mental symptoms in COVID-19infected psychiatric patients.The inflammatory mediators interleukin-6 (IL-6), tumor necrosis factor-a, and IL-10 are considered the main factors inhibiting drug metabolism enzymes, and they have slightly different effects on different cytochrome p450 (CYP) subtypes (26,27).The liver is the main target of IL-6, resulting in decreased activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 (28)(29)(30)(31).Among the antipsychotics used in this study, the key enzymes involved in aripiprazole metabolism are CYP2D6 and CYP3A4 (32, 33).The key enzymes in clozapine are CYP1A2, CYP2C19, and CYP3A4 (34,35).The key enzymes involved in olanzapine are nglucuronaldehyde transferase, flavin monooxygenase, CYP1A2, and CYP2D6 (18,36,37).The key enzymes involved in the action of quetiapine are CYP3A4 and CYP2D6 (28,37,38).The key enzymes involved in risperidone and paliperidone are CYP2D6 and CYP3A4 (39).The key enzymes required for the metabolism of various antipsychotics are blocked by IL-6 to varying degrees, and this may be a possible reason for the decline in the metabolism of various antipsychotics after COVID-19.Moreover, the proportion of patients in the clozapine group with a post-infection drug concentration range exceed that of pre-infection was the highest.This may be related to the inhibition of three key metabolic enzymes of clozapine.Additionally, Hefner et al. confirmed that the plasma concentration of clozapine increased significantly more than that of quetiapine and risperidone Changes in concentration range of antipsychotic drugs post-coronavirus disease-2019 compared to pre-infection.(A) Comparison of antipsychotic drug concentration proportions across three defined levels; (B) Ranking of elevated ratios of drug concentration ranges.
under inflammatory conditions (23).And in the follow-up, we found that clozapine was the highest reduction or discontinuation rate.Besides more significant increase in drug concentration, it may also be related to more side effects caused by clozapine, including sedation, hypersalivation, and increased appetite, compared to other antipsychotics.Therefore, there is a higher probability that patients may tend to omit some of their daily doses while hospitalized.
We compared the elevated concentrations of the different drugs in pairs, and quetiapine demonstrated a reduced risk of elevated concentrations compared with other antipsychotics; therefore, we used quetiapine as the control in the regression analysis.A significant correlation was identified between the drug concentration postinfection and the type of antipsychotic and drug concentration pre-infection, which is consistent with those of previous studies (26,40,41).Our research indicates that the use of traditional Chinese patent medicines among COVID-19 patients with mental disorders may result in elevated concentrations of antipsychotic drugs.However, ibuprofen, compound paracetamol and amantadine hydrochloride, ambroxol, and antibiotics are not associated with an increase in antipsychotic concentrations.It is well known that the use of traditional Chinese patent medicines for treating COVID-19 is widespread in China (42)(43)(44).Therefore, this result emphasizes the importance of exercising caution when using them in treating patients with mental disorders who are also infected with COVID-19.Once administered, it is crucial to promptly monitor the concentrations of antipsychotics and adjust the dosage accordingly.Although drug concentration levels are affected by a combination of factors (for example, inconsistencies in treatment regimens for COVID-19 symptoms, concurrent use of other medications, or the presence of physical illnesses may all serve as confounding factors affecting drug concentrations), the most important factor is the antipsychotic itself, including dose, time of use, and type of drug used.When the baseline drug concentration was subtherapeutic concentration, the post-infection drug concentration was less likely to increase, whereas when the baseline drug concentration was supratherapeutic concentrations, the post-infection drug concentration was more likely to increase.
In addition, we did not find obvious correlation between body temperature, smoking and drug concentration.This is inconsistent with previous studies that have demonstrated that drug concentration is also correlated with individual factors such as age, sex, and smoking (45)(46)(47)(48).Studies have reported that polycyclic aromatic hydrocarbons in tobacco smoke can affect CYP1A2 (49,50) and smokers who take the same dose of clozapine orally have lower concentrations than non-smokers (51)(52)(53).All patients in this study were hospitalized.To reduce the incidence of COVID-19 during the epidemic period in our hospital, cigarettes were totally prohibited from being brought into the ward, so patients couldn't obtain cigarettes during their stay.Therefore, the smokers in this study (94 patients) were in a "quitting smoking" stage when the drug concentration was measured at baseline and post-infection.In a study of 12 heavy smokers by Faber et al., CYP1A2 clearance decreased by 12% on day 1 after quitting and reached a steady state on day 6, with an average clearance 36% lower than before quitting (54).The smokers in this study quit smoking for at least 1 week before the baseline drug concentration was measured, and the influence of smoking and quitting on the concentration was significantly reduced.This may explain why the drug concentration in this study did not correlate with smoking.The increase in drug concentration caused by fever was mainly related to the loss of body fluid.Altogether, 214 patients with fever were included in this study, including 36 cases with high fever (body temperature ≥ 38.5°C) and 178 cases with low fever (37.3°C ≤ body temperature < 38.5°C).Timely fluid rehydration was administered during clinical treatment.Therefore, the reasons for the lack of correlation between body temperature and drug concentration may be as follows.First, the low fever state rarely causes body fluid loss which can lead to increased drug concentration, and the sample size of patients with high fever was small.The sample size could be expanded to further monitor the influence of high and low fever on drug concentration.Second, timely and effective rehydration treatment may compensate for the loss of body fluids caused by fever, resulting in little change in drug concentration.
The regression analysis revealed that pre-infection drug concentration levels, sex, and antipsychotic type were significantly associated with whether patients underwent major antipsychotic dose adjustments.Among them, patients using olanzapine as the primary antipsychotic were less likely to adjust their dose after a drug concentration increase (OR = 0.63, P = 0.0166).Patients receiving clozapine as their primary antipsychotic were more likely to adjust their doses after an increase in drug concentration (OR = 6.58,P < 0.0001).The results for other drugs were not statistically significant.Although the olanzapine concentration also increased post-infection, IL-6 may mainly affected the P450 enzyme system.In addition to CYP1A2 and CYP2D6, olanzapine can complete its metabolic processes via n-glucuronaldehyde transferase, which is weakly affected by inflammatory mediators (55).This also explains why the concentration of olanzapine varied less in patients receiving olanzapine after COVID-19.

Strengths and limitations
The key strengths of our study include the coverage of various antipsychotics.For the first time, we explored the relationship between the concentration of most frequently-used antipsychotics, including clozapine, and COVID-19.The findings of this study can help guide the use of antipsychotics in patients in whom mental disorders are comorbid with COVID-19.This study also has significance as a reference for changes in drug concentrations caused by other viral or bacterial infections.
A major limitation of this study is that we did not exclude changes in drug concentrations caused by drug interactions in the case of multiple antipsychotics, which may explain the differences between this study and other studies.Another limitation is that COVID-19, as a newly discovered virus, causes infections involving the respiratory, digestive, cardiovascular, nervous, and other systems (56, 57).The influence of the patients' physical conditions on the concentration of antipsychotic drugs has not been thoroughly examined.

Conclusion
The concentration of antipsychotics (clozapine, aripiprazole, quetiapine, olanzapine, risperidone, and paliperidone) increased in patients with mental disorders after COVID-19, with clozapine showing the most significant increase.When adjusting the doses of antipsychotics for mental disorders following COVID-19 infection, factors such as the patient's sex, type of antipsychotic, pre-infection drug concentration, and type of drug used for COVID-19 should be considered.Psychiatrists should pay special attention to the use of combined prescriptions when dealing with patients with mental disorders infected with COVID-19, especially when combining traditional Chinese patent medicines, and should closely monitor the concentration of antipsychotic drugs.

TABLE 1
Medical history, therapeutic drugs, and drug concentrations of patients using different antipsychotics.

TABLE 2
Association between drug concentrations post-infection and demographic and clinical factors.

TABLE 3
Association between drug dose adjustment post-infection and demographic and clinical factors.